Sulfur in organic compounds plays a varied and critical role in biological systems. The simple sulfur containing amino acid cysteine is a significant protein building block. It participates in complex metal binding roles, binding to other sulfur groups, protein folding bonding and reduction-oxidation (REDOX) functions. Sulfur atoms are also an important part of amino acid building blocks of peptides, proteins, enzymes, membranes, nucleic acids and DNA.
Many pharmaceutically active compounds (PACs) contain a thiol (sulfhydryl), sulfinyl (SO), sulfonyl (SO2) or sulfonamide (SONR′R′ where R′ is hydrogen or alkyl) group which undergoes oxidation-reduction (REDOX) reactions with thiol (sulfhydryl), disulfide, sulfinyl or sulfonyl groups attached to proteins, enzymes (eg gastric H, K, ATPase), peptides (e.g. glutathione) or simple molecules (eg cysteine). The binding of the PAC to these groups is a reversible process influenced by a number of factors, including pH, presence of other oxidising and reducing groups, physiological REDOX buffer systems, REDOX catalysts, enzymes, and temperature.
In most physiological systems there is a need to maintain a healthy dynamic REDOX balance both inside and outside cells.
The sulfur group of PACs may be particularly important to drug activity. The range of activities of PACs containing sulfur groups cover anti-bacterial, anti-inflammatory, anti-rheumatic, anti-ulcer, anti-viral, anti-psychotic, mucolytic, hepatoprotectant, diuretic, fungicidal, diabetic activities amongst others. The extent of sulfur group content in PACs indicates the biological/pharmacological significance of sulfur content in drug molecules.
Examples of pharmaceutically active compounds (PACs) containing sulfinyl, sulfonyl or sulfonamide groups include proton pump inhibitors (PPIs) and compounds having anti-ulcerant activity, such as Omeprazole, Omeprazole isomers such as S-Omeprazole, Esomeprazole (Nexium®), R-Omeprazole, Lansoprazole, Pantoprazole, Rabeprazole, Pariprazole, Tenatoprazole, Leminoprazole and their isomers or metabolites.
However, despite their biological activity and pharmaceutical benefit, PACs containing sulfur groups are typically relatively unstable, can present formulation difficulties, and/or be of low bioavailability.
Sulfur containing PACs may also be unstable in the acid environment of the stomach. Examples include the proton pump inhibitors (PPIs) such as Omeprazole. Elaborate and costly formulations have been developed and continue to be developed in attempts to address these problems (see for example WO 94/25070, WO 00/27366 and AU 13541/00). Thus, there is a need for a PPI formulation that does not involve an enteric coat but is still stable under stomach acidic conditions.